Method for the synthesis of an aromatic derivative ortho-disubstituted by a halogen atom other than fluorine and by a cyano group

ABSTRACT

The present invention relates to a method for the synthesis of a halogen substituted aryl nitrile, where the halogens are selected from Cl, Br, or I, by reacting an aryl dihalide with a halogen/fluoride exchange reactant to produce a halogen substituted aryl fluoride which is then reacted with a fluoride/cyanide exchange reactant to produce the halogen substituted aryl nitrile.

The instant Application is a 371 of PCT/PR96/02100 filed Dec. 27, 1996.

The present invention relates to a method for the synthesis of anaromatic compound exhibiting an aromatic nucleus comprising at least oneC--C unit substituted on a carbon atom by a cyano group and on the othercarbon atom by a halogen atom other than fluorine.

The cyanation of halogenated aromatic compounds is known, the mostwidely used reaction being the Rosenmund-von Braun reaction, whichachieves the cyanation of chlorinated or brominated aromatics in thepresence of a stoichiometric amount of cuprous ions.

However, the industrial application of this reaction is very awkward andexpensive because it requires effluent treatment operations for thepurpose of separating copper salts and of possible recycling of thetransition metal.

Furthermore, when the intended product is an aromatic compound carryinga cyano group ortho to a halogen substituent, the reaction to be carriedout is a monocyanation of the corresponding orthodihalogenated aromatic.Now, the grafting of a nitrile functional group ortho to a halogen has atendency to promote a second substitution to result in a dicyano, whichis unfavourable to the reaction yield.

In addition, the copper-catalysed Rosenmund-von Braun reaction isgenerally not regioselective with respect to a specific halogen atom.However, a regioselective substitution of a halogen is often observedwhen the latter is ortho to an electron-withdrawing substituent with apredominant mesomeric effect, such as NO₂. In contrast, in the case ofaromatic compounds with a nucleus depleted in electrons by anelectron-withdrawing functional group with a predominant inductiveeffect, the orientation of the substitution is not very marked, muchless than for nuclei depleted by an electron-withdrawing functionalgroup by a mesomeric effect, and problems of regioselectivity can beposed.

The aim of the present invention is to overcome these disadvantages andto provide a method for the synthesis of such an aromatic derivative,disubstituted by a cyano group and a halogen atom arranged in the orthoposition, which makes use of simple and inexpensive reactants, whichdoes not require an effluent treatment operation and which results inthe desired product with a good yield and good selectivity.

Surprisingly, the present Inventors have found that this aim, and otherswhich will become apparent subsequently, can be achieved by a two-stepmethod with great success, both from the yield viewpoint and from theviewpoint of selectivity, in comparison with the conventionalsingle-step method.

In this respect, the subject-matter of the invention is a method for thesynthesis of a compound of formula (I) ##STR1## in which ##STR2## is anoptionally substituted aromatic nucleus depleted in electrons containingat least five carbon-comprising ring members,

and X is selected from Cl, Br and I, characterized in that it comprisesat least the steps consisting in

(a) reacting a compound of formula (II) ##STR3## in which ##STR4## hasthe above meaning and the X substituents, which are identical ordifferent, are selected from Cl, Br and I, with a fluoride-basedhalogen/fluorine exchange reactant, in order predominantly to form acompound of formula (III) ##STR5## and (b) reacting the reaction productof the step (a) with a cyanide-based fluorine/cyanide exchange reactant,in order selectively to form the compound of formula (I).

The reaction of the step (a) generally results in a major isomer offormula (III) and possibly in a minor isomer of formula (IIIb), ##STR6##by monosubstitution by a fluorine atom. It is even possible to observevery good regioselectivity depending on the nature of the compound offormula (II), in particular as a function of other possible substituentsof the aromatic nucleus and of the position of the latter. This will bedescribed in detail subsequently.

The reaction product of the step (a) can, however, comprise a mixture ofisomers, the separation of which is technically very difficult andexpensive to implement on an industrial scale.

Surprisingly, the reaction of the step (b) shows very highchemoselectivity which enhances the selectivity of the overall syntheticsequence in favour of the cyanation product of the isomer of formula(III) and which is unfavourable to the cyanation of the isomer offormula (IIIb). Thus, the step (b) can be carried out on the reactionmixture of the step (a) without separation of the isomers.

In addition, the product of the double cyanation of the compound offormula (III) is not observed and the desired product is obtained withvery good selectivity.

The method of the invention preferably applies to compounds of formula(II) where the two X substituents are identical. Advantageously, each Xis a chlorine atom.

Generally, it is preferable for at least one X to be a chlorine atom.

The aromatic nucleus ##STR7## advantageously comprises 6 ring membersand is in particular a benzene nucleus. It can also comprise at leastone heteroatom.

The possible substituents of the aromatic nucleus can be highly variedin nature, for example carriers of functional groups of use in thecontinuation of the synthetic sequence. They can also be optionallysubstituted alkyl, alkenyl, alkynyl or aryl groups or alkenylene oralkynylene groups connected to the aromatic nucleus in order to form apolycyclic system comprising at least one aromatic nucleus. Mention maybe made, as example of such a nucleus, of a naphthalene nucleus.

The aromatic nucleus of the compound of formula (II) is depleted inelectrons due to the presence of the two X substituents. In addition, itcan be depleted in electrons by an electron-withdrawing functional groupforming a ring member of the said nucleus or by the presence of at leastone substituent carrying an electron-withdrawing functional groupgrafted onto an atom of the said nucleus, or by both these causessimultaneously.

In particular, in the formula (II), ##STR8## can be an aromatic nucleuscomprising at least one heteroatom which depletes in electrons thearomatic nucleus, such as, in particular, nitrogen or phosphorus.

Mention may be made, as examples of such aromatic nuclei, of pyridine orquinoline.

The depletion in electrons can also result from the substitution of thesaid nucleus by at least one electron-withdrawing group.

Such an electron-withdrawing substituent can be selected from groupswhich withdraw by an inductive effect or by a mesomeric effect, asdefined in the reference work in Organic Chemistry "Advanced OrganicChemistry" by M. J. March, 3rd edition, published by Wiley, 1985, inparticular pages 17 and 238. It is preferable, in particular, to avoidgroups carrying a hydrogen atom capable of forming hydrogen bonds, suchas a carboxylic acid group, and groups carrying a basic hydrogen atomwhich can result in a deprotonation, such as an alkyl ketone grouphaving a hydrogen α to the carbonyl.

Mention may be made, as example of suitable electron-withdrawing groups,of the groups --NO₂ ; --CN; --CF₂ R where R is a fluorine atom or ahydrocarbon-comprising radical; --COOR' where R' is ahydrocarbon-comprising radical; --CHO; --Cl; or --Br.

The method of the invention applies particularly advantageously tocompounds of formula (II) in which the electron-depleted aromaticnucleus carries an electron-withdrawing substituent with a predominantinductive effect, these compounds giving poor results in the directreaction of Rosenmund-von Braun type.

Such a substituent is preferably selected from --CN and --CF₂ R groups,where R is selected from a fluorine atom and hydrocarbon-comprisinggroups, advantageously C₁₋₂₀ hydrocarbon-comprising groups, whichpreferably are themselves electron-withdrawing. Thesehydrocarbon-comprising groups advantageously do not comprise a basichydrogen atom which can result in a deprotonation.

A substituent of formula --CY₂ R, where Y, which are identical ofdifferent, are selected from Cl and F and R has the above meaning or isa chlorine atom, can also be used but is capable of reacting in the step(a) to result in chlorine/fluorine exchange.

The said electron-depleted aromatic nucleus advantageously carries onlya single electron-withdrawing substituent. Preferably, on a 6-memberedaromatic nucleus, this substituent is found in the ortho or paraposition with respect to the X atom which is intended to be substitutedin a first step by a fluorine atom in the step (a) to form the majorproduct of formula (III). The presence of such an electron-withdrawinggroup ortho or para to this X atom has the effect of increasing theselectivity of the substitution reaction of the step (a), so that theproduct of formula (III) is greatly in the majority with, respect to theproduct of formula (IIIb), according to the following reactions:##STR9##

Preferably, when the said aromatic nucleus is an aryl, its electrondensity is at most in the region of that of a halobenzene, in particularof a dichlorobenzene.

To obtain satisfactory electron depletion, it is preferable for the sumof the Hammett constants of the electron-withdrawing functional groupscarried by the said aromatic nucleus, either as ring member or assubstituent of the said nucleus, to be between 0.10 and 1.60.

More particularly, it is advantageous for the sum of the Hammettconstants of the substituents of the said aromatic nucleus to be between0.4 and 1, advantageously from 0.5 to 0.8.

In addition, it is advantageous for each substituent other than X tohave a Hammett constant of between 0.2 and 0.7.

For the definition of Hammett constants, reference will be made to thereference work: March--"Advanced Organic Chemistry", third edition, JohnWiley and Son, pages 242 to 250.

By way of example, the method of the invention can be employed with3,4-dichlorotrifluoromethylbenzene in order to synthesize2-chloro-4-(trifluoromethyl)benzonitrile, with a good yield and highselectivity, according to the scheme hereinbelow. ##STR10##

The method of the invention comprises essentially two steps.

In a first step (a), the compound of formula (II) is reacted with ahalogen/fluorine exchange reactant. This reactant is advantageously aninorganic fluoride, preferably selected from alkali metal fluorides, inparticular, from sodium fluoride, potassium fluoride, rubidium fluorideand caesium fluoride. Potassium fluoride is generally preferred foreconomic reasons, although fluorides of alkali metals with an atomicmass greater than that of potassium substantially Strove the reactionyield.

It is also possible to use, as countercation of the fluoride, any cationhaving properties equivalent to those of an alkaline cation, such as,for example, a quaternary ammonium cation.

Numerous methods have been described for carrying out this reaction,such as, for example, those disclosed in the certificate of additionU.S. Pat. No. 2,353,516 and in the article Chem. Ind. (1978), 56, andhave been employed industrially for producing aryl fluorides, aryls onwhich are grafted electron-withdrawing groups.

This reaction can be carried out by heating the reaction components at arelatively high temperature, generally from 200 to 280° C., inparticular in the region of 250° C., in an appropriate solvent.

In an alternative form, the reaction can be carried out at lowertemperature, with a significant improvement in the yield, by subjectingthe reaction mixture to the action of ultrasound.

Generally, the reaction can be carried out at a temperature of 80 to280° C., according to the conditions chosen.

It should be pointed out that the use of ultrasound releases a largeamount of energy within the reaction mixture; this energy substitutes,in all or part, for the heating energy normally required.

The preferred conditions comprise an ultrasound power emitted directlyby the wall providing for this emission at least at 20 W/cm²,advantageously to 50 W/cm², more advantageously to 100 W/cm², preferablyto 200 W/cm².

The frequencies which can be used are those of commercial devices, thatis to say that the frequency of the ultrasound is advantageously between10 and 100 KHz, preferably between 15 and 50. Some frequencies give verysignificantly better results; they correspond to those of resonance ofthe mixture under the conditions of the experiment and are generallycovered by the relatively broad emission spectrum of commercial devices.

The use of ultrasound makes it possible to carry out the reaction atrelatively low temperatures of between 80 and 200° C., preferably from100 to 150° C.

Generally, the reaction preferably takes place in a dipolar aproticsolvent. The relative dielectric constant .di-elect cons. of the saidsolvent is advantageously at least equal to 10, preferably .di-electcons. is less than or equal to 100 and greater than or equal to 25.Preference is particularly given to solvents for which the donor numberD, expressed by the variation in enthalpy (AH in kcal/mol) of thecombination of the said solvent with antimony pentachloride, is from 10to 50.

Advantageous solvents are dimethyl sulphoxide (DMSO), dimethyl sulphone,dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylacetamide(DMAC) and sulpholane (tetramethylene sulphone).

The halogen/fluorine exchange reactant advantageously comprises a solidwhich remains in the form of a solid dispersed in the reaction mixtureand which comprises an alkaline fluoride and optionally a cation whichpromotes the reaction.

The reactant advantageously comprises, as promoter, a heavier alkalinecation than potassium. This alkaline cation can be introduced in theform of a halide and not necessarily in the form of a fluoride. Ingeneral, the alkaline cation is introduced in the form of a chloride.The content of alkaline cation advantageously represents from 1 to 5 mol%, preferably from 2 to 3 mol %, of the fluoride used.

The reaction can comprise, as promoter, agents often described as phasetransfer agents and which are "oniums". The oniums generally representfrom 1 to 10 mol %, preferably from 2 to 5 mol %, of the fluoride.

The oniums are selected from the group of cations formed by elementsfrom Groups VB and VIB (as defined in the Table of PeriodicClassification of the Elements published in the supplement to theBulletin de la Societe Chimique de France in January 1966), with 4 or 3hydrocarbon-comprising chains.

Among oniums deriving from elements from Group VB, the preferredreactants are tetraalkyl- or tetraarylammonium or -phosphonium notexhibiting hydrogen β to the heteroatom. The hydrocarbon-comprisinggroup advantageously comprises from 4 to 12 carbon atoms, preferablyfrom 4 to 8 carbon atoms. Mention may be made, for example, oftetramethylammonium or tetraphenylphosphonium. It is also possible touse compounds of alkylpyridinium type. Oniums deriving from Group VIBare preferably derived from elements with an atomic number greater thanthat of oxygen.

The ultrasound method described above makes it possible advantageouslyto use tetraalkylammonium, which have little stability at a temperaturegreater than approximately 150° C.

The amount of onium generally represents from 1 to 10%, preferably from2 to 5%, of the mass of the inorganic fluoride.

In general, the molar ratio of the said alkaline or ammonium fluoride tothe said substrate is between 0.8 and 1.5, preferably in the region of1.25 times the stoichiometry. It can be advantageous to operate with asubstoichiometric fluoride/substrate ratio (thus an incompleteconversion) because the risks of a double halogen/fluorine exchangereaction capable of taking place when the compound of formula (I) is inthe presence of a large excess of fluorine are thus limited and, underthese conditions, the compound of formula (I) is formed with anexcellent selectivity which improves the selectivity of the overallmethod.

It is also desirable for the water content of the reactant to be at mostequal to approximately 2%, preferably 1%, with respect to the mass ofthe reactant.

Stirring is advantageously carried but so that at least 80%, preferablyat least 90%, of the solids are maintained in suspension by thestirring.

In fact, it is desirable for the greater part of the solids to be insuspension in the reaction mixture.

Thus, the stirring, to meet this restriction, must be neither toovigorous, in order to avoid pressing, by cyclone effects, an excessivelylarge portion of the solids against the wall of the reactor, nor toolow, in order to be capable of causing the solids resulting from thereaction and the solids used as fluorine source to pass into suspension.

The reaction product from the step (a) can be charged in the step (b) assoon as the progress of the first step is deemed to be satisfactory.

"Reaction product" is understood to mean the product of the substitutionreaction of a halogen atom by a fluorine atom on the compound of formula(II). This reaction product generally comprises a mixture of isomersresulting from the substitution of one or other of the X atoms and avery minor amount of difluorination product resulting from thesubstitution of both X atoms, this reaction product predominantlycontaining the compound of formula (III).

According to the invention, the separation of the reaction product fromthe reactants which have not been converted during the step (a) isunnecessary because they will not be affected by the reactant of thestep (b), or else to only a very small extent, to optionally providedesired product of formula (I). Neither is any attempt made to isolatethe products formed and still less the monofluorination isomers.

The reaction mixture obtained at the end of the step (a) can thus becharged as is in the step (b).

Generally, the reaction product, optionally in solution in all or partof the solvent used for the reaction of the step (a), is charged in thestep (b) in the form of a mixture with a fluorine/cyanide exchangereactant.

This reactant advantageously comprises a cyanide selected from cyanidesof metals from Groups I and II, such as, in particular, sodium,potassium, magnesium or calcium, and quaternary ammonium cyanides.Sodium cyanide and potassium cyanide are among the preferred reactants.It is also possible advantageously to use a mixture of potassium cyanideand of calcium chloride, source of calcium cyanide.

The amount of exchange reactant, expressed as mols of cyanide, employedin the step (b) is preferably between 1 and 2 times, advantageouslybetween 1 and 1.5 times, the amount of compound of formula (II) formedin the step (a).

The reaction components are preferably brought together in a polaraprotic solvent. The relative dielectric constant .di-elect cons. of thesaid solvent is advantageously at least equal to 10, preferably.di-elect cons. is less than or equal to 100 and greater than or equalto 25. Preference is particularly given to solvents for which the donornumber D (ΔH in kcal/mol of the combination of the said solvent withantimony pentachloride) is from 10 to 50.

The majority of the solvents which can be used in the step (b) are alsovalid for the step (a). Thus it is that the reaction product of the step(a) can be introduced into the step (b) in its reaction solvent, whichdoes away with any intermediate operation between the steps.

The solvent which can be used for the step (b) can, without problem, beselected from those having a dielectric constant and/or a donor numberof the order of the low limits indicated above, indeed lower than theselimits (solvents of little or very little polarity), such as, forexample, acetonitrile, benzonitrile or crown ethers, allowing for theadditional use of phase transfer agents, such as the "oniums" describedpreviously.

The reaction temperature depends on the nature of the cyanide-basedreactant and the solvent. Generally, a temperature rise accelerates thereaction. The reaction is advantageously carried out between 20 and 250°C.

The reaction takes place readily at atmospheric pressure in aconventional reactor but can also take place in a pressurized reactor,advantageously at a pressure of less than 5×10⁶ Pa.

It is preferable for the reaction mixture to be substantially anhydrous,not only in order to maintain the selectivity of the reaction in favourof the desired isomer but also to limit the corrosion due to thefluoride ions released as reaction by-product.

The presence of a transition metal, in particular copper, in thereaction mixture in the step (b) is not advantageous because thereaction takes place spontaneously. It is even desirable to operate witha copper content as low as possible in order to avoid correspondingseparation and retreatment operations.

The copper content in the reaction system of the step (b) is preferably10⁻² mol.l⁻¹ or less. Advantageously, this content is less than 10⁻³mol.l⁻¹, preferably than 10⁻⁴ mol.l⁻¹.

The copper content can also be expressed with respect to the amount ofthe substrate in the reaction of the step (b). In this case, it ispreferable for the amount of copper present in the reaction system ofthe step (b), expressed as mol, to be less than one tenth,advantageously than one hundredth, very particularly than onethousandth, of the amount of reaction product employed in the step (b),expressed as mol.

The duration of the reaction is determined as a function of the rate offormation of the desired final isomer.

The desired final product of formula (I) present in the reaction mixtureat the end of the step (b) can easily be isolated. The separationtechnique preferably comprises the following two operations:

filtration or distillation, in order to separate the organic compoundsfrom the inorganic salts,

fractional distillation, in order to separate, from the said organiccompounds, the desired product of formula (I), the reactants andreaction products from the step (a) which have not reacted in step (b),and the solvent.

The method according to the invention can comprise the operationsconsisting in:

i) mixing the compound of formula (II) and the X/F exchange reactant ina solvent;

ii) subjecting the mixture thus obtained to heating or to an ultrasoundemission;

iii) optionally separating the solid phase and/or at least a portion ofthe solvent from the reaction mixture obtained in (ii);

iv) adding, to the reaction mixture of ii) or to the residue of theoperation (iii), the F/CN exchange reactant, optionally with an amountof a solvent identical to or different from that of the operation (i);

v) maintaining the contact between the reactants, optionally whileraising the temperature of the mixture;

vi) separating, from the reaction mixture obtained in (v), the solidphase based on inorganic salts;

vii) separating the compound of formula (I) from the remaining liquidphase by fractional distillation.

The inorganic salts separated in (vi) include the unreacted reactant ofthe operation (i) and salts formed by the fluoride ions released by thereaction at the operation (v). These salts can advantageously berecycled in the step (i) in order to be used therein as halogen/fluorineexchange reactant.

As was said above, the two-step method according to the inventionprovides the desired product with a very good yield. The highselectivity of the second step, which could not be anticipated and hasbeen demonstrated by the present inventors, makes it possible directlyto treat the reaction mixture obtained in the step (a) in order toobtain, on conclusion of the step (b), a reaction product comprisingessentially the desired compound of formula (I).

In fact, the two-step method is easy to implement in the context ofindustrial scale production, in so far as it only requires conventionalequipment, if necessary comprising a unit for separation of theintermediates which is particularly simple, and in so far as it makes itpossible to dispense with effluent retreatment units intended to recoversalts of transition metals, such as copper, which are essential in aplant for production by the conventional single-step method.

Furthermore, the cyanation step (b) uses a reactant which is economical,on the one hand, by the low cost of the cyanide salts and, on the otherhand, by the absence of transition metal.

The invention will now be illustrated by the following examples, whichexhibit various reaction conditions which allow the synthesis of2-chloro-4-(trifluoromethyl)benzontrile ##STR11## which is anintermediate of use in the preparation of herbicides, in two steps from3,4-dichlorctrifluoro-methylbenzene.

The results presented in the examples are expressed as a function ofthree quantities which are defined hereinbelow:

the degree of conversion of a reactant R (DCR) is the ratio of theamount (molar) of R which has disappeared during a reaction to theinitial amount of R;

the real production yield of a product P from a reactant R (RYP) is theratio of the amount of P produced to the initial amount of R;

the conversion yield of R to P (CYP), which is the ratio of the amountof P produced to the amount of R which has disappeared.

EXAMPLE 1

A--Synthesis of 3-chloro-4-fluorotrifluoro-methylbenzene

The following reaction is carried out: ##STR12##

35.4 g (0.164 mol) of 3,4-dichlorotrifluoro-methylbenzene A, 11.6 g(0.200 mol) of potassium fluoride, 2.8 g (0.008 mol) oftetra(n-butyl)phosphonium bromide and 44.0 g of sulpholane areintroduced at room temperature, in an anhydrous atmosphere, into a glassreactor equipped with a mechanical stirrer, a fractionation column and areflux condenser.

The reaction mixture is heated and the temperature is maintained at85±2° C.

Distillation begins after approximately 30 minutes and, after a rapiddevelopment, gradually slows down. The reaction is complete after 5hours.

The mixture is purified by fractional distillation in order to recoverthe aromatic fractions and the sulpholane.

The conversion of A is DCA=82.2%

The real yield of C is RYC=66.3%, the conversion yield of A to C, CYC,has the value 80.7%.

The real yield of D is RYD advantageously 8.0%, the conversion yield ofA to D has the value 9.7%,

The conversion thus takes place with an 89% selectivity in favour of Cand an 11% selectivity in favour of D.

B--B synthesis of 2-chloro-4-(trifluoromethyl)-benzonitrile

The following are placed in a reactor:

1 g of the mixture of isomers C and D separated in A (1 mol equivalent)

16.1 g of DMSO (41 mol equivalents)

0.52 g of KCN (1.6 mol equivalents)

The reaction mixture is heated at a temperature of 60° C. for 10 h 15minutes.

Analysis of the final reaction mixture makes it possible to determinethat the reaction corresponds to the following equation with thefollowing results: ##STR13## DCC=94%; DCD=35%; RYE=77%; RYF 11%;CYE=82%; CYF=31%.

C is converted virtually quantitatively (DCC=94%), whereas D isconverted to only a small extent (DCD=35%). The reaction is highlyregioselective.

Furthermore, the conversion of C results mainly in the desired product E(CYE=82%), whereas the conversion of D provides only a small amount offluorine/cyanide exchange product F (CYE=31%).

Consequently, the cyanation reaction provides the desired product veryselectively with respect to its isomer. In fact, the proportion of thedesired isomer E with respect to the cyanation product (E and F),expressed by the molar ratio ##EQU1## which is indicative of theregioselectivity of the reaction, is 98%. As the desired product is veryslightly contaminated by its isomer, from which it is difficult toseparate, it is sufficient to employ simple separation techniques inorder to separate the other reaction by-products and provide achlorocyanotrifluoromethylbenzene derivative of high purity which can beused directly for the purpose of subsequent conversions.

EXAMPLE 2

The step A is carried out as in Example 1 in order to obtain amonofluorination product comprising 89% of C and 11% of D.

The step B is carried out in the presence of 1.4 mol equivalents ofsodium cyanide in DMSO (27 mol equivalents) at a temperature of 90° C.for 2 h 30 min.

The results of the cyanation are presented in the following Table 1, inwhich the operating conditions are summarized.

EXAMPLE 3 to 5

The steps A and B of Example 1 were repeated, apart from slightoperating variations which mainly relate to the solvent, the temperatureand the duration of reaction of the step B. The results are presented inTable 1.

These examples show that it is possible to vary the operating conditionsaccording to the various preferred alternative forms indicated abovewhile still obtaining very good results as regards the yield and theselectivity, in particular if the solvent is DMF or DMSO. Sulpholanerequires slightly severer reaction conditions.

EXAMPLE 6

The step B of Example 1 was repeated on the pure product C(monofluorination product comprising 100% of C) with a cyanationreactant comprising a mixture of KCN and CaCl₂ in the proportion of 1.5molar equivalents of KCN and 0.5 molar equivalent of CaCl₂ per one molarequivalent of C.

The degree of conversion and the conversion results are presented inTable 1, in which the operating conditions are recalled. The conversionis slightly lower than in Example 1 but the conversion yield is higher,so that the yield of the desired reaction is comparable with that ofExample 1.

EXAMPLE 7

The step B of Example 1 was repeated on the pure product C with 1.5molar equivalents of sodium cyanide NaCN in N-methylpyrrolidone (16molar equivalents). Like sulpholane, NMP requires relatively severeconditions. However, a very good conversion and a satisfactory reactionyield are obtained.

The data of this example are collated in Table 1.

EXAMPLE 8

The step B of Example 1 was repeated on the pure product C with 1.9molar equivalents of KCN in acetonitrile (11 molar equivalents) in thepresence of tetrabutylammonium bromide as phase transfer agent (0.08molar equivalent).

The results of this test, presented in Table 1 with the operatingconditions, are once again highly satisfactory.

                                      TABLE I                                     __________________________________________________________________________             STEP B                                                                    STEP                                     E                                  A                                                                            Example C/D  Solvent Reactant Temperature Duration DCC  DCD  RYE  CYE                                                     E + E                             No. Ratio (eq.) (eq.) (° C.) (h) % % % % %                           __________________________________________________________________________    1    87/13                                                                             DMSO (41)                                                                           KCN (1.6)                                                                             60    10.25                                                                              94 35 77 82 98                                2 89/11 DMSO (27) NaCN (1.4) 90 2.5 97 27 79 81 98                            3 89/11 DMF (22) KCN (1.8) 80 13 90 53 71 79 98                               4 90/10 DMF (37) KCN (1.7) 60 30 85 32 66 80 99                               5 89/11 Sulpholane KCN (1.7) 100  13.5 88 43 65 73 99                           (56)                                                                        6 100/0  DMF (32) KCN (1.5) + 80 10.35 88 -- 76 86 --                            CaCl.sub.2 (0.5)                                                           7 100/0  NMP (16) NaCN (1.5) 105  4.5 96 -- 70 73 --                          8 100/0  MeCN (11) KCN (1.9) + 82 30.0 94 -- 63 66 --                            Bu.sub.4 N.sup.+ Br.sup.-  (0.08)                                        __________________________________________________________________________

What is claimed is:
 1. Method for the synthesis of a compound of formula(I) ##STR14## in which ##STR15## is an optionally substitutedsix-membered aromatic nucleus depleted in electrons, said nucleuscomprising at least five carbon atoms,and X is selected from Cl, Br andI, characterized in that it comprises at least the steps comprising(a)reacting a compound of formula (II) ##STR16## in which ##STR17## has theabove meaning and the X substituents, which are identical or different,are selected from Cl, Br and I, with a fluoride-based fluorine/halogenexchange reactant, the reaction resulting in a compound of formula (III)##STR18## present as the major product in the reaction mixture, and (b)reacting the reaction product from the step (a) directly with acyanide-based fluorine/cyanide exchange reactant to form, the compoundof formula (I).
 2. Method according to claim 1, wherein, in the compoundof formula (II), the two X substituents are identical.
 3. Methodaccording to claim 2, wherein each X represents a chlorine atom. 4.Method according to claim 1, wherein, in the compound of formula (II),is an aromatic nucleus ##STR19## comprising at least one heteroatom. 5.Method according to claim 1, wherein the said aromatic nucleus isadditionally substituted by at least one electron-withdrawing group. 6.Method according to claim 1, wherein the said aromatic nucleus issubstituted by at least one electron-withdrawing group with apredominant inductive effect.
 7. Method according to claim 6, whereinsaid electron-withdrawing group with an inductive effect is selectedfrom the --CN and --CF₂ R groups, where R is selected from a fluorineatom and hydrocarbon-comprising groups.
 8. Method according to claim 5,wherein said aromatic nucleus is substituted by a singleelectron-withdrawing group.
 9. Method according to claim 1, wherein saidwithdrawing group is in the ortho or para position with respect to the Xatom to be substituted.
 10. Method according to claim 1, wherein the sumof the Hammett constants of the electron-withdrawing functional groupscarried by the said aromatic nucleus is between 0.10 and 1.60. 11.Method according to claim 1, wherein the sum of the Hammett constants ofthe substituents of the said aromatic nucleus is between 0.4 and
 1. 12.Method according to claim 1, wherein the Hammett constant of each of thesubstituents of the said aromatic nucleus other than X is between 0.2and 0.7.
 13. Method according to claim 1, wherein the halogen/fluorineexchange reactant of the step (a) is an inorganic fluoride, inparticular an alkali metal fluoride, or quaternary ammonium fluoride.14. Method according to claim 1, wherein the amount of fluorine employedin the step (a) is between 0.8 and 1.5 times the amount of compound offormula (I).
 15. Method according to claim 1, wherein the reaction ofthe step (a) is carried out at a temperature of 80 to 280° C.
 16. Methodaccording to claim 1, wherein the reaction mixture obtained at the endof the step (a) is charged as is in the step (b).
 17. Method accordingto claim 1, wherein the said fluorine/cyanide exchange reactant of thestep (b) comprises a cyanide selected from cyanides of metals fromGroups I and II and quaternary ammonium cyanides.
 18. Method accordingto claim 1, wherein the amount of cyanide employed in the step (b) isbetween 1 and 1.5 times the amount of compound of formula (III) formedin the step (a).
 19. Method according to claim 1, wherein the coppercontent in the reaction mixture of the step (b) is 10⁻² mol.l⁻¹ or less.20. Method according to claim 1, wherein the amount of copper present inthe reaction system of the step (b), expressed as mol, is less than orequal to one tenth of the amount of reaction product of the step (a)employed in the step (b), expressed as mol.
 21. Method according toclaim 1, wherein fluoride released by the fluorine/cyanide exchangereaction and optionally fluoride which has not reacted in the step (a)is isolated in the step (b) and is recycled in the step (a) ashalogen/fluorine exchange reactant.
 22. Method according to claim 7wherein said hydrocarbon-comprising groups are electron-withdrawinghydrocarbon-comprising groups.